Case Report

A 48 year old otherwise healthy postmenopausal status, postvaginal hysterectomy woman was prescribed estradiol transdermal spray (Ther-Rx Corp, St Louis, MO) to help alleviate vasomotor symptoms of menopause. She began applying 2 sprays (1.53 mg estradiol each) to her inner left forearm, as directed in the package insert, each morning. After approximately 3 months of application, she noticed that the left areola had become darker and now differed in color from the right areola. She then discontinued use on the left arm and began applying the spray to the right arm instead. The right areola began to darken until it was the same color as the left at which point she began applying the spray bilaterally, 1 spray on each forearm, with now continued consistency in pigmentation between areola. She denied any other change in pigmentation elsewhere.

Comment

This is an interesting and unanticipated side effect of unilateral application of a transdermal medication. Estrogens are known to incite melanogenesis, which is commonly observed during pregnancy and in the use of oral contraceptives. Dermal estrogens initially were reported to cause intense pigmentation of the mammary areola, linea alba of the abdomen and genitals, mammary enlargement, and the presence of pubic hair in infants.

More recently in vitro cultured melanocytes were found to have an up-regulation of enzymes of melanogenesis in the presence of estradiol. Likewise, estrogen receptor expression was increased in skin affected by melasma as compared with unaffected skin in 2 subjects. A 48 year old menopausal female who was receiving ultraviolet B light therapy had hyperpigmentation that occurred at the site of her estradiol patch.

Following epidermal application of the medication, estrogens are absorbed through the skin and enter superficial venous and lymphatic vessels of the forearm. These vessels drain to the cephalic and axillary lymphatics, which lead to the axillary lymph nodes. The skin of the breast, including the areola, also drains to these lymph nodes.

Ipsilateral hyperpigmentation seen in this case could be related to the shared venous and lymphatic drainage of the forearm and breast.

The contralateral areola is not affected because the right upper limb is drained by the right lymphatic duct, whereas the left upper limb is drained by the thoracic duct. This separation of lymph vessels for the upper extremities prohibits the medication from affecting the contralateral areola. In our patient, applying the medication to both forearms corrected this discrepancy of pigmentation.